Use of sultines in the asymmetric synthesis of polypropionate antibiotics

At low temperature and in the presence of an acid catalyst, SO2 adds to 1,3-dienes equilibrating with the corresponding 3,6-dihydro-1,2-oxathiin-2-oxides (sultines). These compounds are unstable above -60 degrees C and equilibrate with the more stable 2,5-dihydrothiophene 1,1-dioxides (sulfolenes). The hetero-Diels-Alder additions of SO2 are suprafacial and follow the Alder endo rule. The sultines derived from 1-oxy-substituted and 1,3-dioxy-disubstituted 1,3-dienes cannot be observed at -100 degrees C but are believed to be formed faster than the corresponding sulfolenes. In the presence of acid catalysts, the 6-oxy-substituted sultines equilibrate with zwitterionic species that react with electron-rich alkenes such as enoxysilanes and allylsilanes, generating beta,gamma-unsaturated silyl sulfinates that can be desilylated and desulfinylated to generate polypropionate fragments containing up to three contiguous stereogenic centers and an (E)-alkene unit. Alternatively, the silyl sulfinates can be reacted with electrophiles to generate polyfunctional sulfones (one-pot, four-component synthesis of sulfones), or oxidized into sulfonyl chlorides and reacted with amines, then realizing a one-pot, four-component synthesis of polyfunctional sulfonamides. Using enantiomerically enriched dienes such as 1-[(R)- or 1-(S)-phenylethyloxyl-2-methyl-(E,E)-penta-1,3-dien-3-yl isobutyrate, derived from inexpensive (R)- or (S)-1-phenylethanol, enantiomerically enriched stereotriads are obtained in one-pot operations. The latter are ready for further chain elongation. This has permitted the development of expeditious total asymmetric syntheses of important natural products of biological interest such as the baconipyrones, rifamycin S, and apoptolidin A.

Transition metal-catalyzed carbon-carbon cross-coupling reactions using sulfonyl derivatives

The goal of this thesis was to find conditions to form C-C double bond and single bond using sulfonyl derivativies, which are arising from the Vogel's oxyallylation cascades. In a second chapter, it is shown that 2-methylprop-2-ene-1-sulfonyl fluorides can be easily prepared via the ene reaction of methallylsilanes and SO2 followed by halogenosis (NCS, then KF). In the presence of a base, aldehydes and 2-methylprop-2-ene-1-sulfonyl fluorides give mixture of (1Z)- and (1E)-1-aryl-3-methylbutadienes. Their (Z)→(E) isomerization by classical means fails or leads to their polymerization. We have discovered that SO2 can isomerize 1-aryl-3-methyl-1,3-dienes at low temperature, without formation of sulfolenes (cheletropic addition/elimination). Preliminary mechanistic studies suggest that SO2 add to the 1,3-dienes forming 1,4-diradical intermediates that are responsible for the (Z)→(E) isomerizations. In the third chapter, we have shown that arenesulfonyl chlorides are versatile electrophilic reagents for C-C cross-coupling reactions. Arene-, arylmethane- and alk-2-ene-1-sulfonyl chlorides undergo desulfitative Stille, carbonylative Stille, Negishi and Suzuki-Miyaura cross-coupling reactions. In these reactions the reactivity order is ArI> ArSO2Cl> ArBr> ArCl. Similarly, desulfitative Sonogashira-Hagihara cross-couplings of arenesulfonyl chlorides with aryl- and alkylacetylenes can be catalyzed by Pd2(dba)3/P(t-Bu)3/CuI. New conditions have been found for the desulfitative Mizoroki-Heck arylation and trifluoromethylation of mono- and disubustituted olefins with arenesulfonyl and trifluoromethanesulfonyl chlorides. This procedure allows one to obtain (E)-1,2-disubstituted alkenes with high stereoselectivity and 1,1,2-disubstituted alkenes with high (E)/(Z) stereoselectivity. If phosphine- and base-free conditions are required, 1 mol% {RhCl(C2H4)2} catalyses the desulfitative cross-coupling reactions. On the contrary to what has been reported for RuCl2(PPh3)2 catalyzed coupling reactions with sulfonyl chlorides, the palladium and rhodium desulfitative Mizoroki-Heck coupling reactions are not inhibited by radical scavenging agents. Moreover, sulfones that are formed from the sulfonylation of alkenes at 60°C can theoretically be envisaged as intermediates in all cross-coupling reactions. However we have shown that they are not desulfitated at higher temperatures in the presence of the Pd or Rh-catalysts. Alk-2-ene-1-sulfonamides can also undergo desulfamylating cross-coupling reaction with Grignard reagents in the presence of a nickel catalyst. In the fouth chapter, we have evaluated the possibility that silyl sulfinates can be used as nucleophilic partners to form C-C bond. Our preliminary results indicate that their hypothesis should be explored further. In a fifth chapter, we have contributed to the development of an efficient one-pot, three component syntheses of sulfonamides and sulfonic esters. We have demonstrated that the ene-reaction of sulfur dioxide with enoxysilanes can be stereoselective under conditions of kinetic control. As others in our laboratory, we have shown that the hetero-Diels-Alder addition of sulfur dioxide to 1-oxy or 1,3-dioxy-1,3-dienes generates zwitterions that add to enoxysilanes or allylsilanes giving silyl sulfinates that can be converted in the same pot into polyfunctional sulfones, sulfonamides or sulfonic esters. Intramolecular S-allylation of intermediate silyl sulfinates has allowed one to prepare new tetrahydro-2H-thiocine derivatives. Our key contribution has been to use enantiomerically enriched amines which has allowed one to obtain enantiomerically enriched polyfunctional sulfonamides.

EPFL2005

Umpolung with Sulfur Dioxide: Carbon-Carbon Cross-Coupling of Electron-Rich 1,3-Dienes and Alkenes; Application to the Enantioselective Synthesis of Long-Chain Polyketide Fragments

Claudia Jana Exner, Maris Turks, Pierre Vogel

At low temperature and in the presence of an acid catalyst, sulfur dioxide undergoes hetero-Diels-Alder additions with 1-oxy-1,3-dienes, giving unstable sultines, which are ionized into zwitterionic species and react as 1-oxyallylic cation intermediates (Umpolung with SO2) with electron-rich alkenes such as allylsilanes or enoxysilanes. The (beta,gamma-unsaturated silyl sulfinates so-obtained can be desulfinylated in situ to generate polyketide fragments containing up to three contiguous stereogenic centers in one-pot operations. This reaction cascade can be applied in two-directional chain elongation approaches for the asymmetric synthesis of long chain polyketide fragments using 1-[(S)- or (R)-1-phenylethoxy]1,3-dienes.

2009

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Cotinica Craita

Under appropriate conditions sulfur dioxide reacts with 1,3-dienes in a hetero-Diels-Alder fashion. In the case of 1-alkoxy-1,3-dienes the 6-alkoxy-3,6-dihydro-1,2-oxathiin-2-oxides (sultines) so-obtained can be ionized in the presence of Lewis or protic acids. The zwitterionic intermediates can be trapped as electrophiles with enoxysilanes (oxyallylation) to generate substituted silyl alkenylsulfinates. The latter can then be reacted with TBAF and an electrophile to generate polyfunctional sulfones (one pot, four component syntheses). Alternatively, desilylation through silicon/palladium transmetallation, in the presence of a catalytic amount of Pd(OAc)2, leads to intermediate allylsulfinic acids, which, after retro-ene desulfitation, produce 4-alkoxyhept-6-en-2-one core, a valuable fragment in polyketide natural product synthesis. The first part of this work described the application of an asymmetric version of this new SO2 reaction cascade, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade), using enantiomerically enriched dienes. The synthesis of a variety of β-alkoxy ketones was realized with good α,β-syn selectivity, starting from different enoxysilanes, illustrating the versatility of the method. An iterative Vogel's cascade employing newly obtained fragments provided long-chain polypropionate fragments such as (-)-(4R,5R,6S,9S,10R,2E,11E)-4,6,10-trimethyl-5,9-bis-((1S)-1-phenylethoxy)-trideca-2,11-dien-7-one in a very short and efficient way. The synthetic potential of Vogel's cascade reaction was demonstrated by the short and elegant synthesis of the enantiomerically enriched polypropionate fragment (C16-C28) of apoptolidinone, aglycon of apoptolidin, a highly potent apoptosis inducing agent. In the second part of thesis the one pot polyfunctional sulfone synthesis, developed in our group was successfully combined with the aldol methodology of Paterson to reach an advanced polyketide fragment, a potential intermediate in the total synthesis of Restricticin. Finally, in the last part of this study, we have demonstrated that methallyl silylsulfinates, known as new reagents for alcohol silylation are very precious and efficient reagents for the silylation of phenols and carboxylic acids. Additionally, the chemoselectivity of these reagents on substrates containing different hydroxyl groups was demonstrated.

EPFL2006

Total asymmetric synthesis of advanced polyketide fragments of apoptolidinone and rectricticin using new organic chemistry of sulfur dioxide

Cotinica Craita

EPFL2006

Transition metal-catalyzed carbon-carbon cross-coupling reactions using sulfonyl derivatives

EPFL2005